Amino acid (AA) arterial blood plasma concentrations, K1 (peripheral production + infusion rates), and central plasma clearance rates (K1 : arterial concentration) (CPCR-AA) were measured in 70 seriously septic patients. All of these people were in the 'hyperdynamic' state at the time of observation. Thirty-seven recovered and 33 died. In addition, 10 noninfected, nontraumatized patients about to undergo laparotomy were studied. In 31 patients receiving parenteral alimentation, CPCR-AA was 326 ± 38 in survivors and 160 ± 17 ml/M2/min in the deaths (p<0.005). In 58 patients studied, while fasted with no intravenous amino acid infusion, values for CPCR-AA were: survivors 202 ± 22 (28) and deaths 112 ± 16 (30) ml/M2/min (p<0.002). The CPCR-AA in 10 noninfected patients was only 68 ± 11 ml/M2/min. CPCR-AA in 19 patients correlated with hepatic protein synthetic rates in liver biopsies obtained simultaneously (r = 0.658, p<0.01), which shows that CPCR-AA is an indicator of visceral protein synthesis. To study the regulation of amino acid metabolism by proteolysis inducing factor (PIF), the proteolysis inducing activity (PIA) of the plasma fraction (0-50,000 D) was measured 55 times in conjunction with metabolic studies. No significant differences existed in PIA between survivors and deaths. However, in those patients who recovered, PIA was significantly correlated to both peripheral amino acid production (r = 0.773, p<0.001) and to CPCR-AA (r = 0.721, p<0.001). This observation demonstrates the presence of one or more circulating agents affecting amino acid flux. PIA measured simultaneously in vivo correlated with in vitro protein synthetic rate in incubated liver biopsies (r = 0.653, p<0.01). PIF (4,000 D), isolated by chromatography, in patients without amino acid infusion was 35 ± 3% in survivors and 33 ± 6% in deaths (N.S.) and only 9 ± 3% over control in noninfected patients. In patients who recovered, PIF titre was strongly correlated with peripheral amino acid production (r = 0.798, p<0.001) and with CPCR-AA (r = 0.835, p<0.001). However, values for patients who later died were significantly less for a given PIF titre. Thus, it is concluded that survival from sepsis is, in part, dependent on a significantly elevated CPCR-AA and hepatic protein synthesis, both of which appear to be related to the blood plasma PIF titre. Since PIF is the circulating active cleavage product of interleukin-1 produced by macrophages, PIF appears to be the hormone-like link between the immunological system and metabolism.